Taking STEPs forward to understand fragile X syndrome

Results Probl Cell Differ. 2012:54:223-41. doi: 10.1007/978-3-642-21649-7_12.

Abstract

A priority of fragile X syndrome (FXS) research is to determine the molecular mechanisms underlying the functional, behavioral, and structural deficits in humans and in the FXS mouse model. Given that metabotropic glutamate receptor (mGluR) long-term depression (LTD) is exaggerated in FXS mice, considerable effort has focused on proteins that regulate this form of synaptic plasticity. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase implicated as an "LTD protein" because it mediates AMPA receptor internalization during mGluR LTD. STEP also promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn, thereby opposing synaptic strengthening. We hypothesized that dysregulation of STEP may contribute to the pathophysiology of FXS. We review how STEP's expression and activity are regulated by dendritic protein synthesis, ubiquitination, proteolysis, and phosphorylation. We also discuss implications for STEP in FXS and other disorders, including Alzheimer's disease. As highlighted here, pharmacological interventions targeting STEP may prove successful for FXS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alternative Splicing
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / anatomy & histology
  • Brain / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / enzymology*
  • Fragile X Syndrome / physiopathology*
  • Gene Expression Regulation, Developmental
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Amyloid beta-Peptides
  • Isoenzymes
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Fragile X Mental Retardation Protein
  • Proto-Oncogene Proteins c-fyn
  • Extracellular Signal-Regulated MAP Kinases
  • PTPN5 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor